Summary: Morphine derivatives of the methanobenzazocine family that act as potent analgesics.

Top Publications

  1. Parenti C, Turnaturi R, Aricò G, Marrazzo A, Prezzavento O, Ronsisvalle S, et al. Antinociceptive profile of LP1, a non-peptide multitarget opioid ligand. Life Sci. 2012;90:957-61 pubmed publisher
    ..LP1, a multitarget opioid ligand, is a supraspinal acting antinociceptive agent that is useful for the treatment of chronic pain. ..
  2. Ahmed M, Mather A, Enna S. Binding of [3H]desglycinyl remacemide to rat brain membranes: association with the benzomorphan attachment site of the N-methyl-D-aspartic acid receptor channel. Brain Res. 1999;827:46-50 pubmed
    ..In contrast, haloperidol, and other sigma receptor-active agents, were relatively inactive at this site. These data suggest that DGR interacts with a channel blocking site on the NMDA receptor. ..
  3. Laird J, Carter A, Grauert M, Cervero F. Analgesic activity of a novel use-dependent sodium channel blocker, crobenetine, in mono-arthritic rats. Br J Pharmacol. 2001;134:1742-8 pubmed
    ..These data suggest that up regulation of sodium channel expression in primary afferent neurones may play an important role in the pain and hyperalgesia induced by joint inflammation...
  4. Tamura T, Taniguchi T, Miyamoto T, Aoki M, Waki I. Effects of eptazocine, a novel analgesic, on KCN-induced changes in the cerebral contents of glycolytic metabolites and high-energy phosphates in mice. Jpn J Pharmacol. 1990;54:179-85 pubmed
    ..These results suggest that eptazocine may improve anoxic changes in cerebral energy metabolism. ..
  5. Christoffers K, Khokhar A, Chaturvedi K, Howells R. Inhibition of mu and delta opioid receptor ligand binding by the peptide aldehyde protease inhibitor, leupeptin. Regul Pept. 2002;105:9-14 pubmed
    ..We propose that leupeptin inhibits ligand binding by reacting reversibly with essential sulfhydryl groups that are necessary for high-affinity ligand/receptor interactions. ..
  6. Russell K, Moore T, Potter D. Elevation of atrial natriuretic peptide levels in aqueous humor of the rabbit by kappa opioid receptor agonists. Neuropeptides. 2001;35:232-7 pubmed
    ..In summary, BRE and SPR increased ANP levels in aqueous humor of rabbits, in part, via activation of K+(ATP) channels that are assumed to be associated with kappa opioid receptors. ..
  7. Gue M, Pascaud X, Honde C, Junien J, Bueno L. Peripheral antagonistic action of trimebutine and kappa opioid substances on acoustic stress-induced gastric motor inhibition in dogs. Eur J Pharmacol. 1988;146:57-63 pubmed
  8. Craft R, Picker M, Dykstra L. Differential cross-tolerance to opioid agonists in morphine-tolerant pigeons responding under a schedule of food presentation. J Pharmacol Exp Ther. 1989;249:386-93 pubmed
  9. Zhang A, Xiong W, Hilbert J, DeVita E, Bidlack J, Neumeyer J. 2-aminothiazole-derived opioids. Bioisosteric replacement of phenols. J Med Chem. 2004;47:1886-8 pubmed
    A series of aminothiazole-derived morphinans, benzomorphans, and morphine were synthesized...

More Information


  1. Amarante L, Duarte I. The kappa-opioid agonist (+/-)-bremazocine elicits peripheral antinociception by activation of the L-arginine/nitric oxide/cyclic GMP pathway. Eur J Pharmacol. 2002;454:19-23 pubmed
    ..Our data suggest that bremazocine elicits peripheral antinociception by activation of the L-arginine/NO/cyclic GMP pathway and that nitric oxide is an intermediary in this mechanism, forming cyclic GMP. ..
  2. Trost B, Tang W. Migratory hydroamination: a facile enantioselective synthesis of benzomorphans. J Am Chem Soc. 2003;125:8744-5 pubmed
    We describe a highly efficient, general strategy for the enantioselective synthesis of benzomorphans (45-46% overall yield from commercially available material)...
  3. Pasquinucci L, Turnaturi R, Prezzavento O, Arena E, Aricò G, Georgoussi Z, et al. Development of novel LP1-based analogues with enhanced delta opioid receptor profile. Bioorg Med Chem. 2017;25:4745-4752 pubmed publisher
    ..p., respectively. Moreover, the antinociceptive effect of compound 9 was longer lasting with respect to LP1. In conclusion the N-substituent nature of compounds 6, 7 and 9 shifts the DOR profile of LP1 from antagonism to agonism. ..
  4. Sandrini M, Romualdi P, Capobianco A, Vitale G, Morelli G, Pini L, et al. The effect of paracetamol on nociception and dynorphin A levels in the rat brain. Neuropeptides. 2001;35:110-6 pubmed
    ..Paracetamol seems to exert its antinociceptive effect also through the opioidergic system modulating dynorphin release in the central nervous system (CNS) of the rat, as suggested by the decrease in the peptide levels. ..
  5. Kumru S, Simsek M, Yilmaz B, Sapmaz E, Kutlu S, Sandal S, et al. Differential regulation of preovulatory luteinizing hormone and follicle-stimulating hormone release by opioids in the proestrous rat. Physiol Res. 2001;50:397-403 pubmed
    ..In conclusion, we suggest that the secretion of LH and FSH is differentially regulated by mu- and kappa-opioid receptors. It is thought that in all groups chloral hydrate interfered with the LH surge secretory systems. ..
  6. Mamede Rosa M, Prado W. Antinociception induced by opioid or 5-HT agonists microinjected into the anterior pretectal nucleus of the rat. Brain Res. 1997;757:133-8 pubmed
    ..These results indicate that the antinociceptive effects of opioid or serotonergic agonists microinjected into the APtN depend on drug interaction with local mu or 5-HT1B receptors, respectively. ..
  7. Friese N, Chevalier E, Angel F, Pascaud X, Junien J, Dahl S, et al. Reversal by kappa-agonists of peritoneal irritation-induced ileus and visceral pain in rats. Life Sci. 1997;60:625-34 pubmed
    ..These data suggest that selective kappa-opioid receptor agonists might be used to treat abdominal pain associated with motility and transit impairment during postoperative ileus. ..
  8. Stevenson G, Folk J, Linsenmayer D, Rice K, Negus S. Opioid interactions in rhesus monkeys: effects of delta + mu and delta + kappa agonists on schedule-controlled responding and thermal nociception. J Pharmacol Exp Ther. 2003;307:1054-64 pubmed
    ..These results also confirm that opioid agonist interactions may depend on the receptor selectivity and relative doses of the agonists and on the experimental endpoint. ..
  9. Bakalkin GYa -, Kobylyansky A. Opioids induce postural asymmetry in spinal rat: the side of the flexed limb depends upon the type of opioid agonist. Brain Res. 1989;480:277-89 pubmed
    ..In most animals, neurons with a higher specificity to some agonist are localized on one side of the sagittal plane. ..
  10. Pineyro G, Azzi M, deLéan A, Schiller P, Bouvier M. Reciprocal regulation of agonist and inverse agonist signaling efficacy upon short-term treatment of the human delta-opioid receptor with an inverse agonist. Mol Pharmacol. 2005;67:336-48 pubmed
    ..Taken together, these data show that inverse agonists may induce rapid regulation in receptor signaling efficacy. ..
  11. Fjalland B, Christensen J. Kappa-opioid receptor agonists differentially affect the release of neurohypophysial hormones. Pharmacol Toxicol. 1990;66:176-8 pubmed
    ..The data support the theory of an inhibiting endogenous control over oxytocin secretion and show that the release of oxytocin and vasopresin is differentially affected by the two K-receptor agonists. ..
  12. Mulder A, Burger D, Wardeh G, Hogenboom F, Frankhuyzen A. Pharmacological profile of various kappa-agonists at kappa-, mu- and delta-opioid receptors mediating presynaptic inhibition of neurotransmitter release in the rat brain. Br J Pharmacol. 1991;102:518-22 pubmed
    ..6 for naloxone. 5. Thus, whereas U69593 and PD1 17302 display high potency and selectivity towards K-opioid receptors, the potent benzomorphan K-agonists bremazocine and EKC also appear to be strong mu-opioid receptor antagonists. ..
  13. Amarante L, Alves D, Duarte I. Study of the involvement of K+ channels in the peripheral antinociception of the kappa-opioid receptor agonist bremazocine. Eur J Pharmacol. 2004;494:155-60 pubmed
    ..On the basis of these results, we suggest that K(+) channels are not involved in the peripheral antinociceptive effect of bremazocine, although this opioid receptor agonist induces nitric oxide/cGMP pathway activation. ..
  14. Barrett A, Cook C, Terner J, Roach E, Syvanthong C, Picker M. Sex and rat strain determine sensitivity to kappa opioid-induced antinociception. Psychopharmacology (Berl). 2002;160:170-81 pubmed
    ..Similar to data obtained with micro opioids, the magnitude of these sex differences was generally larger with the less effective kappa opioids and determined, in part, by rat strain and nociceptive stimulus intensity. ..
  15. Husbands S, Neilan C, Broadbear J, Grundt P, Breeden S, Aceto M, et al. BU74, a complex oripavine derivative with potent kappa opioid receptor agonism and delayed opioid antagonism. Eur J Pharmacol. 2005;509:117-25 pubmed
    ..The slow onset, long-duration kappa opioid receptor agonist effects of BU74 suggests that it could be a lead compound for the discovery of a treatment for cocaine abuse. ..
  16. Dortch Carnes J, Potter D. Bremazocine: a kappa-opioid agonist with potent analgesic and other pharmacologic properties. CNS Drug Rev. 2005;11:195-212 pubmed
    ..In addition, the ability of bremazocine-like drugs to lower intraocular pressure and to minimize ischemic damage in animal models suggests their possible use in the therapy of glaucoma and cardiovascular disease. ..
  17. Gonzalez Nunez V, Barrallo A, Traynor J, Rodriguez R. Characterization of opioid-binding sites in zebrafish brain. J Pharmacol Exp Ther. 2006;316:900-4 pubmed
    ..Hence, the study of zebrafish opioid activity may contribute to an understanding of endogenous opioid systems in higher vertebrates. ..
  18. Collins S, Gerdes R, D Addario C, Izenwasser S. Kappa opioid agonists alter dopamine markers and cocaine-stimulated locomotor activity. Behav Pharmacol. 2001;12:237-45 pubmed
    ..In addition, treatment with the kappa-opioid agonist U-69593 (0.32 mg/kg) over a 5-day period decreased dopamine transporter densities in the caudate putamen, and this was also blocked by co-administration of naltrexone. ..
  19. Craft R, Dykstra L. Agonist and antagonist activity of kappa opioids in the squirrel monkey: II. Effect of chronic morphine treatment. J Pharmacol Exp Ther. 1992;260:334-42 pubmed
    ..Changes in antagonist activity of kappa opioids after chronic morphine administration may be explained by concurrent changes in their agonist potency and the extent to which their agonist effects are mu-mediated. ..
  20. Vanderschuren L, Schoffelmeer A, Wardeh G, de Vries T. Dissociable effects of the kappa-opioid receptor agonists bremazocine, U69593, and U50488H on locomotor activity and long-term behavioral sensitization induced by amphetamine and cocaine. Psychopharmacology (Berl). 2000;150:35-44 pubmed
    ..By influencing dopaminergic neurotransmission, opioid drugs can alter the behavioral effects of psychostimulants...
  21. Dykstra L, Massie C. Antagonism of the analgesic effects of mu and kappa opioid agonists in the squirrel monkey. J Pharmacol Exp Ther. 1988;246:813-21 pubmed
    ..43 and 7.61, respectively; whereas the pA2 value for quadazocine in combination with bremazocine and U50,488 were 6.53 and 6.43, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  22. Iwamoto E. Evidence for a model of activation of central sigma systems. Life Sci. 1989;44:1547-54 pubmed
    ..5 mg/kg of MR2266. The data suggest that the manifestation of the (+)-BUT/(-)-NAN-induced syndrome depends upon intact transmission at central sigma sites. ..
  23. Reid A, Mattson M, de Costa B, Thurkauf A, Jacobson A, Monn J, et al. Specificity of phencyclidine-like drugs and benzomorphan opiates for two high affinity phencyclidine binding sites in guinea pig brain. Neuropharmacology. 1990;29:811-7 pubmed
    ..These clinical observations, in conjunction with the present biochemical binding data, suggest that (+)MK801 may serve as a "marker" for site 1 and that the psychotomimetic effects of phencyclidine might be mediated by site 2. ..
  24. Picker M, Cook C. Discriminative stimulus effects of opioids in pigeons trained to discriminate fentanyl, bremazocine and water: evidence of pharmacological selectivity. Behav Pharmacol. 1997;8:160-73 pubmed
    ..e. two-choice tasks). In this task, however, the level of kappa antagonist activity evidenced by these opioids was considerably less than that obtained in pigeons trained to discriminate bremazocine from saline. ..
  25. Grauert M, Bechtel W, Ensinger H, Merz H, Carter A. Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as antagonists of the NMDA receptor-channel complex. J Med Chem. 1997;40:2922-30 pubmed
    ..HCl [(2R)-[2 alpha, 3(R*),6 alpha]-1,2,3,4,5,6-hexahydro-3-(2-methoxypropyl)-6,11,11-trimethyl -2,6-methano-3-benzazocin-9-ol hydrochloride] was chosen as the optimum candidate for further pharmacological investigations. ..
  26. Ko M, Willmont K, Lee H, Flory G, Woods J. Ultra-long antagonism of kappa opioid agonist-induced diuresis by intracisternal nor-binaltorphimine in monkeys. Brain Res. 2003;982:38-44 pubmed
    ..More important, this study provides functional evidence for a homogenous population of KOR underlying KOR-mediated diuresis and illustrates a unique pharmacological profile of nor-BNI-induced ultra-long KOR antagonism in vivo. ..
  27. Carter A, Grauert M, Pschorn U, Bechtel W, Bartmann Lindholm C, Qu Y, et al. Potent blockade of sodium channels and protection of brain tissue from ischemia by BIII 890 CL. Proc Natl Acad Sci U S A. 2000;97:4944-9 pubmed
    ..Our results demonstrate that BIII 890 CL is a potent, selective, and highly use-dependent Na(+) channel blocker that protects brain tissue from the deleterious effects of focal cerebral ischemia in rodents. ..
  28. Tamura T, Taniguchi T, Aoki M, Waki I. [Protective effect of eptazocine, a novel analgesic, against cerebral hypoxia-anoxia in mice]. Nihon Yakurigaku Zasshi. 1990;95:167-75 pubmed
    ..These results suggest that eptazocine elicited its cerebral protective effect via its binding with opioid kappa-receptors and probably an activation of the central cholinergic system. ..
  29. Rabkin S. The opioid agonist ethylketocyclazocine accentuates epinephrine-induced cardiac arrhythmias in the rat through an action in the brain. Brain Res Bull. 1993;31:427-32 pubmed
    ..These data indicate that EKC, through an action in the brain, modulates cardiac arrhythmias and suggests a role for opioid receptor agonists, such as EKC, in cardiac arrhythmias and perhaps sudden cardiac death in man. ..
  30. Picker M, Negus S, Powell K. Differential cross-tolerance to mu and kappa opioid agonists in morphine-tolerant rats responding under a schedule of food presentation. Psychopharmacology (Berl). 1991;103:129-35 pubmed
    ..The present findings demonstrate that the chronic administration of morphine results in the selective development of tolerance to other mu agonists.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  31. Piepponen T, Mikkola J, Ruotsalainen M, Jonker D, Ahtee L. Characterization of the decrease of extracellular striatal dopamine induced by intrastriatal morphine administration. Br J Pharmacol. 1999;127:268-74 pubmed
    ..Tolerance develops to this inhibitory effect during repeated morphine treatment. Furthermore, our results suggest that the effect of intrastriatally-administered morphine is mediated by the micro-opioid receptors. ..
  32. Pasquinucci L, Iadanza M, Marrazzo A, Prezzavento O, Ronsisvalle S, Scoto G, et al. New benzomorphan derivatives of MPCB as MOP and KOP receptor ligands. Pharmazie. 2007;62:813-24 pubmed
    ..Evaluation of docking simulations of compounds 9 and 28 into the KOP and MOP receptor displayed selective ligand interactions with the important amino acid residues Tyr320 (TMVII) and Trp318 (TMVII), respectively. ..
  33. Million M, Fioramonti J, Bueno L. Oral administration of Tyr-MIF-1 stimulates gastric emptying and gastrointestinal motility in rodents. Peptides. 1992;13:469-74 pubmed
    ..These data demonstrate that oral Tyr-MIF-1 stimulates gastric emptying and gastrointestinal motility through a systemic or central action that involves opioid and GABA systems. ..
  34. Bonner G, Meng F, Akil H. Selectivity of mu-opioid receptor determined by interfacial residues near third extracellular loop. Eur J Pharmacol. 2000;403:37-44 pubmed
    ..We conclude that a primary role for Trp(318) is to form a basis for ligand selectivity. ..
  35. Neumeyer J, Bidlack J, Zong R, Bakthavachalam V, Gao P, Cohen D, et al. Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives: mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine dependence. J Med Chem. 2000;43:114-22 pubmed
    ..Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist. ..
  36. Pasquinucci L, Prezzavento O, Marrazzo A, Amata E, Ronsisvalle S, Georgoussi Z, et al. Evaluation of N-substitution in 6,7-benzomorphan compounds. Bioorg Med Chem. 2010;18:4975-82 pubmed publisher
    ..LP1, possessing a mu/delta agonist profile, could represent a lead in further developing benzomorphan-based ligands with potent in vivo analgesic activity and a reduced tendency to induce side effects. ..
  37. Tiberi M, Magnan J. Pharmacological characterization of the binding of [3H]bremazocine in guinea-pig brain: evidence for multiplicity of the kappa-opioid receptors. Can J Physiol Pharmacol. 1989;67:1336-44 pubmed
    ..abstract truncated at 250 words) ..
  38. Clarke S, Czyzyk T, Ansonoff M, Nitsche J, Hsu M, Nilsson L, et al. Autoradiography of opioid and ORL1 ligands in opioid receptor triple knockout mice. Eur J Neurosci. 2002;16:1705-12 pubmed
    ..Labelling of the ORL1 receptor with [3H]nociceptin showed region-dependent quantitative increases in triple knockout brains indicating a close relationship between the two systems in specific brain areas. ..
  39. Bolger G, Marcus K, Thibou R, Skolnick P, Weissman B. Enhancement of [3H]DAGO1 binding to rat brain by low concentrations of monovalent cations. Can J Physiol Pharmacol. 1987;65:2338-45 pubmed
    ..3H]etorphine binding increased and was unchanged, and both [3H]bremazocine and [3H]naloxone binding increased by 50 mM Na+ in 5 mM and 50 mM Tris-HCl, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  40. Dortch Carnes J, Potter D. Effect of bremazocine, a kappa-opioid receptor agonist, on inositol phosphate formation in isolated iris-ciliary bodies. Pharmacology. 2002;66:100-6 pubmed
    ..Thus, opioid agonist-induced increases in IP activity could play a role in BRE-induced increases in atrial natriuretic peptide release and alterations in aqueous humor dynamics. ..
  41. Cosgrove K, Carroll M. Effects of bremazocine on self-administration of smoked cocaine base and orally delivered ethanol, phencyclidine, saccharin, and food in rhesus monkeys: a behavioral economic analysis. J Pharmacol Exp Ther. 2002;301:993-1002 pubmed
    ..These results extend the findings that kappa-agonists reduce the self-administration of drug and nondrug reinforcers to smoked cocaine base and oral ethanol, PCP, and saccharin in rhesus monkeys. ..
  42. Schomburg E, Steffens H, Wada N. Parallel nociceptive reflex pathways with negative and positive feedback functions to foot extensors in the cat. J Physiol. 2001;536:605-13 pubmed
    ..e. it mediates a positive feedback. ..
  43. Adams J, Teal P, Sonders M, Tester B, Esherick J, Scherz M, et al. Synthesis and characterization of an affinity label for brain receptors to psychotomimetic benzomorphans: differentiation of sigma-type and phencyclidine receptors. Eur J Pharmacol. 1987;142:61-71 pubmed
    Brain sigma-type receptors and phencyclidine receptors are thought to mediate the psychotomimetic effects of benzomorphans and phencyclidine in humans...
  44. de Costa B, Rice K, Bowen W, Thurkauf A, Rothman R, Band L, et al. Synthesis and evaluation of N-substituted cis-N-methyl-2-(1-pyrrolidinyl)cyclohexylamines as high affinity sigma receptor ligands. Identification of a new class of highly potent and selective sigma receptor probes. J Med Chem. 1990;33:3100-10 pubmed
    ..Furthermore, these compounds also exhibited enantioselectivity ranging from 5-fold for (+)- and (-)-44 to 160-fold for (+)- and (-)-29. Several other compounds showed equivalent selectivity but displayed lower sigma receptor affinity. ..
  45. Christoffers K, Li H, Howells R. Purification and mass spectrometric analysis of the delta opioid receptor. Brain Res Mol Brain Res. 2005;136:54-64 pubmed
  46. Voorn P, Brady L, Schotte A, Berendse H, Richfield E. Evidence for two neurochemical divisions in the human nucleus accumbens. Eur J Neurosci. 1994;6:1913-6 pubmed
    ..Our results demonstrate the presence of at least two neurochemically distinct divisions within the human nucleus accumbens, which may be homologous to the 'shell' and 'core' divisions of the nucleus as found in the rat. ..
  47. Collins S, D Addario C, Izenwasser S. Effects of kappa-opioid receptor agonists on long-term cocaine use and dopamine neurotransmission. Eur J Pharmacol. 2001;426:25-34 pubmed
    ..In addition, U-69593 can block cocaine-induced locomotor effects without major perturbation of the dopamine system. ..
  48. Barker W, Worm K, Dolle R. High-performance liquid chromatographic enantioseparation of methanobenzazocines. J Chromatogr A. 2009;1216:7708-14 pubmed publisher
    ..In the case of 1,5-methano-3-methyl-6-phenyl-1,2,3,4,5,6-hexahydro-3-benzazocine only a dinitrophenyl substituted beta-cyclodextrin produced a separation of enantiomers. ..
  49. Ko M, Johnson M, Butelman E, Willmont K, Mosberg H, Woods J. Intracisternal nor-binaltorphimine distinguishes central and peripheral kappa-opioid antinociception in rhesus monkeys. J Pharmacol Exp Ther. 1999;291:1113-20 pubmed
    ..Moreover, it provides a valuable pharmacological basis for further characterizing different sources of kappaOR-mediated effects, namely, from central or peripheral nervous system receptors. ..
  50. Xu W, Chen C, Huang P, Li J, de Riel J, Javitch J, et al. The conserved cysteine 7.38 residue is differentially accessible in the binding-site crevices of the mu, delta, and kappa opioid receptors. Biochemistry. 2000;39:13904-15 pubmed
  51. Craft R, Dykstra L. Agonist and antagonist activity of kappa opioids in the squirrel monkey: I. Antinociception and urine output. J Pharmacol Exp Ther. 1992;260:327-33 pubmed
  52. Rusovici D, Negus S, Mello N, Bidlack J. Kappa-opioid receptors are differentially labeled by arylacetamides and benzomorphans. Eur J Pharmacol. 2004;485:119-25 pubmed
    ..receptors, historically defined by their pharmacological selectivity for either arylacetamides or benzomorphans are, in fact, different affinity states or binding sites on the same kappa-opioid receptors...
  53. Iwama T, Ishihara K, Takagi H, Satoh M. Possible mechanism involved in the inhibitory action of U-50, 488H, an opioid kappa agonist, on guinea pig hippocampal CA3 pyramidal neurons in vitro. J Pharmacobiodyn. 1987;10:564-70 pubmed